Germicide



tats

GERMICIDE Leon F. Shackell, 8 Albert Ave., Morristown, NJ.

2 Claims. (Cl. 167-'31) The present invention relates to a method ofreducing, inhibiting or tempering the corrosive action of a causticphenol on tissues of the vertebrates in particular, and to compositionsthus obtained, wherein useful characteristics of such a phenol areretained, while its corrosive action is reduced or eliminated.

The present application consists of matters divided out of my originalapplication, Serial No. 536,054, filed May 17, 1944, now abandoned; saidapplication disclosing nitrogenous and non-nitrogenous agents for use inreducing the corrosiveness of caustic phenols. The use ofnon-nitrogenous agents for that purpose is claimed in my copendingdivisional application, Serial No. 115,955, filed September 15, 1949,now Patent No. 2,854,375. In the present application the claims aredirected to nonelected spcies of nitrogenous agents in said originalapplication. Accordingly, the present specification (exclusive' ofclaims) is intended to be a substantially exact duplicate of thespecification in said orignal application except for the omissionherein, so far as seems practicable, of references to non-nitrogenouscausticity-reducing agents that are disclosed in said originalapplication. Omissions therefrom are indicated herein by tripleasterisks The local corrosive action of a phenol is most marked in themonohydroxyphenols, at least those that are not substantially insolublein water. Carbolic acid, the isomeric cresols and their halogenderivatives are typical examples of highly caustic phenols. Although theisomeric xylenols and phenylphenols and thedihydroxyphenols-pyrocatechol, resorcinol and hydroquinone possessdecidedly lower causticities, they exhibit the same type of response tothe causticity-reducing agents herein described as do the highly causticphenols.

In order to prevent confusion, in the description herein a'fter, betweenthe generic term phenol" and the specific compound, C H OH, the latterwill be referred to by its common designation of carbolic acid. Inaddition to the caustic phenols that I have mentioned in the paragraphnext above, I intend to include also in the generic term caustic phenolnot only individual phenols of that class-whether pure, technically pureor crudebut also mixtures thereof, as well as commercial preparationscontaining the same, such as the so-called tar acids, cresylic acid,cresylic creosote, carbolic oil, wood creosote and other wood-tar andcoal-tar distillates containing substantial proportions of one or morespecies of the caustic phenols.

The chief characteristics of the local corrosive action of a causticphenol on the skin are well known. If, for

example, a drop of tricresol or of liquified carbolic acid --i.e.,crystals thereof liquefied by admixture with about a en 2,937,971Patented May 24, 1960 2 less at this point the phenol is washed olf,preferably with ordinary (ethyl or grain) alcohol, the action of thephenol goes on to cause local necrosis to a variable depth in the skin.This so-called burn is slow to heal; not uncommonly leading .to theformation of white scar tissue.

Although carbolic acid for many years has furnished a yardstick-namely,the phenol coeflicient-for measuring the'bacteriostatic and germicidalactivities of a great variety of chemical agents, its caustic, corrosiveand escharotic action upon the intact skin and upon other animal tissueshas limited greatly its use in the local treatment of common infectionsand infestations of the skin of man and the lower animals, such aspimples, incipient boils, ringworm, mange, pediculosis and the like. Thesame disadvantage attaches generally to the other caustic phenolsmentioned above.

Apparently as a direct result of the corrosiveness of such phenols,substantially all of the search for improved, phenol-type germicides anddisinfectants has been directed to the synthesis of coal-tar derivativespossessing as high phenol coefiicients and as low toxicities-systemicand local-as possible.

A principal object of my invention is to provide a method of reducingthe corrosive action of a caustic phenol while at the same time avoidinga proportionate reduction in other characteristic activities of thephenol.

A correlative principal object of my invention is to provide acomposition of matter, including a phenol and a causticity-reducingagent therefor, whereby the corrosive activity of the phenol is loweredto an extent that is disproportionately great in comparison to anyreduction in other characteristic activities.

Another object of my invention is to provide a method of reducing thecorrosiveness of a caustic phenol while avoiding any essentialalteration in the molecular structure of the phenol.

Another object is to provide a composition of matter,

including a physical mixture of a caustic phenol and acausticity-reducing agent therefor, whereby the causticity of the phenolis reduced without involvement of any substantial chemical interactionbetween the phenol and the causticity-reducing agent.

Another object is to provide a composition of matter, including acaustic phenol and a phenol-tempering agent which is adapted to inhibitthe causticity of the phenol when present in the mixture in an equal orminor proportion, by weight, relative to the phenol.

Another object is to provide a substantially Water-free composition ofmatter, including a caustic phenol and a tempering agent therefor, thecomposition being adapted for local application to the human skin, aswell as to the skin of lower animals, whereby without injuring the skinto effect destruction of organisms responsible for various cutaneousdisorders.

Another object is to provide a composition of matter, containing acaustic phenol and a causticity-reducing agent therefor, wherein thereduction in causticity of the phenol is disproportionately great incomparison with any reduction in the value of its phenol coefiicient.

Another object is to provide, at lower cost than that of prior artphenolic preparations used for like purposes, a substantially water-freecomposition adapted for use as a germicide, a fungicide, a disinfectantor an insecticide, composing a physical mixture of a caustic phenol anda causticity-reducing' agent therefor; the relative utilities of theseveral preparations being correlated with their respective causticitiesin computing their comparative costs.

Another object is to provide a substantially non-caustic compositioncontaining a chemically unchanged caustic phenol in a concentrationlying" within a wide range of percentages; the composition stillpossessing useful characteristics of the untempered phenol.

Another object is to provide a composition of matter, containing acaustic phenol and a causticity-reducing agent therefor, wherein thereduction in causticity of the phenol is disproportionately great inrelation to the degree of dilution of the phenol with thecausticity-reducing agent.

Another object is to provide a substantially water-free, safelyhandleable liquid mixture of a caustic phenol and a causticity-reducingagent therefor, the mixture being adapted to effect sterilization ofsurgical instruments and like metallic objects immersed therein, butbeing free from any tendency to cause rusting or other metalliccorrosion that may occur in the presence of water.

Other objects and uses of my invention will appear as the descriptionthereof proceeds.

For perhaps fifty years a non-corrosive, liquid mixture of equal partsof carbolic acid crystals and gum camphor has been known under the nameof camphor-phenol. In 1933 US. Patent No. 1,924,169 was granted to JohnE. Stacey for an antiseptic preparation comprising a mixture of camphorand one of the cresols.

That camphor-phenol has been, and still is, considered to be a uniquesystem, is evidenced by the fact that as recently as September 1941, A.W. Francis reported the results of an extended physico-chemical study ofcamphor-phenol mixtures (Journal of American Pharmaceutical Association,vol, 30, pages 229 to 240). Francis refers therein to the Stacey patent.He concludes that his experimental data point to molecular associationbetween camphor and phenol.

As far as I am aware, only two compounds, other than camphor-namely,glycerol and menthol-have been used to form antiseptic preparations withcarbolic acid.

Glycerite phenol-one part liquefied carbolic acid mixed with four partsof glycerolis a long-known preparation,listed formerly in the US.Pharmacopoeia and now in the National Formulary.

I understand that menthol recently has been employed as a substitute forcamphor in camphor-phenol.

For a period of some fifteen years prior to my dis-- covery of theprinciple embodied in my novel method and compositions, I had employedcamphor-phenol for aborting boils as Well as for the treatment of otherskin disorders. A marked disadvantage, however, of camphor-phenol is thegreat volatility and ready sublimation of the camphor at ordinarytemperatures. The result is rapid evaporation of the camphor-phenol,necessitating repeated applications of the mixture to the part beingtreated.

In attempting to obviate this disadvantage of camphorphenol, and yet toform a composition comprising a similar physical mixture of a causticphenol with a causticity-reducing agent, so that the mixture still wouldexhibit high germicidal activity, I have discovered that a great manymaterials of wide variety, which are made up of polar molecules in asuitable state of polarizanon-i.e., molecules containing one or morepolar radicals of certain types possess the property of inhibiting thecorrosive action of the caustic phenol on the skin. Consistent with thisdiscovery I have found out also that so-called nonpolar, hydrocarbonmolecules-as exemplified by benzene, p-xylene, cyclohexane, andpineneexhibit no detectable causticity-reducing activity, other than anyslight effect of that character attributable to dilution of the causticphenol.

In extending my studiesalong this line I have tested many hundreds ofcompounds to determine broadly what types of substances will, and whatwill not, effect a suitable tempering of a caustic phenol withoutforming a reaction product therewith.

At this point it will sufiice to say that I have found, in general, thatpolar compounds wherein the polar radicals are anionoid,electron-donating or nucleophilic in character, are particularlyeffective in reducing the corrosiveness of a caustic phenol. Laterherein is a considerable list of such radicals. The term polar radical,"as used herein, comprehends not only a polar group comprising aplurality of atoms, but also a single atom, where the latter contributesto the state of polarization or polarizability of a polar material.

Polar compounds, on the other hand, wherein the polar radicalsare solelyor preponderantly cationoid, electron-accepting or electrophilic incharacter, exhibit little, if any, capacity to temper a caustic phenol.Typical examples of such cationoid radicals are halogeno and nitro. Ihave found, for instance, that the following cationoid compounds areunsuited for use as polar materials in the practice of my invention:Amylene dichloride; chlorobenzene; o-dichlorobenzene; nitrobenzene;l-nitropropane; 2-nitropropane; s-tetrachlorethane; tetrachlorethylene.

I have found, however, that polar compounds, which contain both anionoidand cationoid radicals, may be effective causticity-reducing agents,provided, that their state of molecular polarization or polarizabilityis preponderantly anionoid in character. That a large enough number ofunsaturated carbon atoms in a compound may sufiice to overcome theelfects of a cationoid radical is evidenced by that fact thato-nitrodiphenyl and l-nitronaphthalene are fairly elfectivecausticity-reducing agents, whereas nitrobenzene is not.

Unless otherwise indicated by the context, I intend my use herein of theterm "polar material to denote a compound (or mixture of compounds) themolecular structure'whereof includes one or more anionoid polar radicalswhich impart to the compound (or mixture of compounds) the property ofphysically affecting the molecules of a caustic phenol in such a mannerthat the causticity of the phenol is reduced or inhibited; othercharacteristics of the phenol, however, remaining substantiallyunaflected.

As I shall point out hereinafter, in discussing my theory of themechanism involved, I ascribe the reduction in causticity to orientationpolarization of the phenol molecules induced by the molecules of aneffective polar material.

As subgeneric to the term polar material I shall use synonymously hereinthe terms causticity-reducing agent, phenol-tempering agent andphenol-polarizing agent. I preferably employ the last of these terms forareason that will appear later herein.

The general characteristics that a polar material should possess inorder to render it suitable for use in the practice of my invention are(a) that it shall be chemically compatible with one or more causticphenols, i.e., that it shall undergo no substantial chemical reaction(in the conventional sense) with the caustic phenol, or phenols, atatmospheric pressure, at temperatures below C., and in the absence of acondensing agent or other catalyst; (b) that it shall be capable offorming a substantially homogeneous physical system or mixture with anequal or greater weight of the caustic phenol, and (c) that its state ofpolarization shall be such as to enable it to reduce the causticity ofthe phenol below the causticity of the same phenol in a control mixturewherein the polar material is substituted by a substantially nonpolarliquid hydrocarbon functioning as a solvent or misicible diluent for thephenol.

Wherever I use the term of the character described with reference to apolar material or phenol-polarizing agent,.I intend the term just quotedto comprehend char- I contemplate as embodying my invention, ordinarilywill be liquids at or about room temperatures. Occasionally,

however, I have formed operative embodiments'ofmy invention whichappear, respectively, as solids, as p'astes, and as creams.

The character of a composition, embodying my invention, as a physicalsystem or mixture, may be demon-' trated by suitable tests known to theart; for example, by the ready separation from the composition of themore volatile ingredient thereof-whether it be the caustic phenol or thephenol-polarizing agent-either as the result of spontaneous evaporationor of distillation. For instance, a number of mixtures that I haveprepared have begun to exhibit caustic efiects only after spontaneousevaporation of a large part of the phenol-polarizing agent, whichhappened to be more volatile than the phenol. As examples thereof I maymention 1:1 mixtures of carbolic acid with each of the followingcompounds: Amyl borate, butyl alcohol, heptaldehyde, butyl acetate,ethyl carbonate, butyl ether, diethyl ketone and capronitrile.

Conversely, I have found that certain of my novel compositions-whereinthe respective phenol-polarizing agents were substantially nonvolatilesolids-could be left in contact with the skin, without eliciting anysign of caustic effect, until the caustic phenol had disappearedtherefrom, leaving a finely granular residue of the polar material. Asan example thereof I may mention a liquid composition consisting of amixture of 2 parts of carbolic acid crystals and one part ofp-acetophenetide.

I have found that the etiectiveness of a given polar material inreducing the escharotic action of a caustic phenoli.e., itstissue-necrosing or most corrosive type of actionmay be testedaccurately and with substantial rapidity on the human subject, while yetavoiding the danger of causing a phenol burn or any permanentdisfigurement. The test may be either quantitative or qualitative or acombination of the two.

The quantitative test comprises a determination of the extent to whichthe polar material is able to delay the onset of initial or earlycaustic effect of the phenol, as exemplified by a burning sensation, orloss of sensibility to skin pain, or whitening of the skin.

The qualitative test involves observation of the degree to which any oneor more of these early caustic efiects is checked or inhibited, or evencompletely abolished. For example, a mixture of a caustic phenol and aparticular polar material may induce some loss of sensibility to skinpain, and yet elicit no sensation of burning. Again, as I have indicatedpreviously, I have made up many compositions embodying my invention,wherein the causticity of the phenol apparently had been inhibitedcompletely, as evidenced by entire absence of any indicia of causticityduring a test period which ended with the disappearance of the phenolfrom the test sample.

My preferred method of testing the efiicacy of a given polar material asa causticity reducing or tempering agent involves primarily themeasurement of sensibility to skin pain as afiected by the composition,embodying my invention, which is being tested. Before I describe mypreferred method of test, however, I shall discuss briefly the termsensibility to skin pain.

In the technique of a neurologic examination it is a standard medicalprocedure to test for sensibility to skin pain by light exploratorypricks with the point of a needle or pin. In the case of a normal,intact skin a light pin prick, which is quite insufiicient to puncturethe skin, will elicit a fleeting subjective sensation of sharpness, orskin pain. Cessation of function in the sensory nerve supply to a patchof skinas by mechanical injury, disease, or the action of a localanesthetic-results in the loss of sensibility to a pin prick; acondition for which the desigplete analgesia, may exist. Such adiminution commonlyis termed hypalgesia.

In testing the capacity of a given polar material to reduce thecausticity 'of a-phenol, I preferably employ the iollowing'metho'dz Isay, of the forearm or of the anterior surface of the thigh, whendisposed horizontally. The time is noted. Then the subject observeswhether or not the mixture causes any sensation of burning. If asensation of sharp burning occurs within one or two minutes, the test isterminated immediately; that is, the mixture is brushed or scraped offif solid, or is blotted with soft paper tissue, if liquid; and theafiected area of skin is sponged off atleast three times with alcohol.Rubbing alcohol is suitable. a

Where a burning sensation rapidly follows upon the application of themixture to the skin, its disappearance after washing otf of the mixtureordinarily is succeeded by a transient erythema and hypalgesia. I

If no burning is felt, nor whitening of the skin is observed, within thefirst two minutes of the test, then the subject (or an observer) pricksthe skin lightly two or three times with the point of a needle or pin;passing the point through the mixture. If the pricks elicit no sensoryresponse (analgesia), or if there is a definite blunting of sensation(advanced hypalgesia or incomplete analgesia)-best determined by testingthe adjacent, untreated skin in a similar mannerthe test ordinarily isterminated in the manner above described.

If, however, the first pricking trials indicate no definite diminutionof sensibility to skin pain, they are repeated at intervals of two orthree minutes until either analgesian (or at least advanced hypalgesia)is demonstrable, or until the test has continued for 15 minutes withoutany perceptible diminution of pain sensibility.

scribed.

Where 15-minute trials" have elicited negative results,-

I have carried out more rigorous tests with each of numerouscompositions embodying my invention; each composition containing atleast 50 percent of (originally) caustic phenol. I have permitted eachsuch composition to remain in contact with the skin until disappearanceof the phenol, either by volatilization or absorption, leaving behind insome instances a relatively nonvolatile residue of the phenol-polarizingagent. I already have given examples of the formation of suchnonvolatile residues in connection with my previous discussion of thephysical character of mixtures embodying my invention.

None of the more rigorous tests just referred tosome lasting for morethan an hourresulted in anything approaching a phenol burn; and in mostinstances the sole observable result was a transient erythema. It

was very seldom, in fact, that one of my novel compo-- initely irritantaction on rather prolonged contact with the skin, I consider that anerythema, without more, re-' sulting from a 15-minute causticity test ofone of my novel compositions, does not warrant any conclusion other thanthat the composition so tested was devoid of caustic activity, at leastfor the period of test.

On the basis of many hundreds of tests that I have carried out, Iconsider that a polar'material is adapted to reduce the corrosiveness ofa caustic phenol if a substantially homogeneous physical system,consisting of one part of the polar material in admixture with one partor more of the phenol, when tested on the human.

skin in the manner described, either elicits no burning sensation orexhibits a delay in the timeof onset ofcaustic effect-whether measuredsubjectively by'a burning' sensation, by hypalgesia, or by analgesia, orobjec-f tively by whitening of the skin-in comparison with the time ofonset of the caustic elfect of a control mixture consisting of a likeproportion of the same phenol and a substantially nonpolar liquidhydrocarbon adapted as a solvent or a miscible diluent therefor.

The hydrocarbon used in making up a control mixture should be capable offorming a homogeneous mixture with at least an equal weight of thecaustic phenol. In general, the aliphatic hydrocarbons, because of theirlimited miscibility with the caustic phenols, are not suitable diluentsfor forming control mixtures. I have tested the following hydrocarbons,however, and have found them to be satisfactory in this respect:Cyclohexane; pinene; p-xylene; xylenes (mixed). The last was atechnically pure grade of xylene, consisting of a mixture of the m-, andp-isomers.

With all control mitxtures that were tested the onset of caustic actionwas detected by a burning sensation. When this sensation became welldefined or sharpwhich occurred in a few seconds after it was firstobserved-the control mixture was washed away in the manner describedabove. 1

V In Example 1 beloware given representative results of tests withcontrol mixtures, each made up of equal weights of the caustic phenoland the hydrocarbon solvent or diluent.

All quantities, parts, proportions or ratios of ingre dients givenherein are in terms of weight. Furthermore, having reference to thecomposition of one of my novel mixtures, and unless otherwise indicated,the first member of each numerical ratio stated herein-say 1:1 orl:3-denotes the parts by weight of polar material, and the second memberdenotes the parts by weight of caustic phenol.

Example 1.-Control mixtures (1:1) of caustic phenols with substantiallynonpolar hydrocarbons;

Onset of burning, seconds Phenol Hydrocarbon diluent Oyclohexane PineneOarbolic acid Do p-Xylcne Xylenes (mixed) Pinen e Xylenes (mixed)-Pinene Xylenes (mixed) o 2,4-Dichlorophenol. Do

I ordinarily consider that a polar material meets characteristic (0),stated above, if, in a ratio to a caustic beyond the time of onsetthereof, as observed in the case of a control mixture-similar to thoseillustrated in Example lcontaining the same caustic phenol.

My preferred practice of the method which embodies my invention varies,depending upon whether the caustic phenol, as well as the selectedcausticity-reducing agent, is a solid or liquid at ordinarytemperatures. The majority of such phenols, when substantially pure,occur as crystalline solids. The latter melt, however, at temperaturesWell below 100 C., and, for the most part, below 50 C. In the presenceof small amounts of impurities--for example in the so-called practicalor technical grades-the caustic phenols commonly exist as liquids. Thelatter also is true of some mixtures of isomeric phenols, as exemplifiedby commercial tricresol, which is a mixture of o-, mand p-cresol.

In reducing the causticity of a phenol which is solid at roomtemperature I prefer to melt a known weight thereof by any suitablemethod which does not raise the temperature of any part of the phenolabove about 95 C. A water-jacketed kettle which is not attacked by thephenol, nor by the causticity-reducing agent to be incorporatedtherewith, is convenient. The container should be provided with meansfor heating the water in the jacket and with suitable mechanism forstirring the contents of the kettle. To the molten phenol in the kettleis added a predetermined quantity of the selected causticity-reducingagent, irrespective whether the latter is in solid or in liquid form.If, upon stirring, the mixture does not readily form a homogeneousliquid, the temperature of the water in the jacket is raised to a pointnot substantially higher than is required to effect formation of ahomogeneous liquid; and in no event higher than about C. The resultingphysical mixture may then be drawn off into bottles or other suitablecontainers provided with closures.

With the great majority of physical mixtures thus formed, the weightratio of phenol to causticity-reducing agent is shown to have been keptwithin a suitable range, if, upon standing for a few days in a closedcontainer at room temperature the mixture remains liquid and shows noseparation of ingredients in solid form. If the causticity-reducingagent is naturally a liquid, and a crystalline phenol was employed inmaking the mixture any solid phase subsequently separating therein mostprobably will be an excess of phenol, which will call for a suitableadditional weight of the causticity-reducing agent; for the separatedphenol will exhibit substantially the same degree of causticity asuntempered phenol.

If, on the other hand, the causticity-reducing agent originally was asolid, and some of the latter separates as a solid phase from itsmixture with the phenol, then the liquid mixture may be separated fromthe polar mate rial by decantation or filtration; or the excess of thephenol-polarizing agent may be liquefied by incorporating therewith asuitable proportion of the phenol, with the aid of a proper degree ofheat, as previously described. 1

An alternative method of preparing compositions embodying my invention,when both the phenol and the polar material are solids at ordinarytemperatures, is to grind together suitable quantities of the respectiveingredients in a triturating device, such as a ball mill or colloidmill.

When the phenol and the polar material are liquids at ordinarytemperatures, the forming of a physical mixture thereof may suitably beeffected by stirring together, without the aid of heat, predeterminedquantities of the respective ingredients.

In order to utilize the benefits attaching to the high concentrations ofcaustic phenols, which I preferably employ in my novel compositions, Iordinarily do not incorporate therewith any inert, or otherwisecompatible, diluent. Nevertheless, where deemed desirable, I may dilutea composition embodying my invention with any suitable nonpolar or polarmaterial. For example, I may dilute the composition with any suitableliquid hydrocarbon, or I may use as a diluent an additional quantity ofthe same polar material that I have employed as a phenol-polarizingagent in making in the composition. I may employ also as a diluent anyone of numerous liquid cationoid compounds which alone are not suitableas phenol-polarizing agents; for example, halogenated hydrocarbons,nitroparaflins, phenyl ether, and the like.

Again, I may, if desired, make a cream, an unguent, a paste or a friablepowder out of a liquid embodiment of my invention by suitableincorporation therewith of one or more compatible materials, known tothe pharmaceutical art, such as an animal or vegetable fat, starch,talc, bentonite, kieselguhr, wood flour, and the like.

Many of the novel compositions embodying my invention contain preferably50 percent or more of caustic phenol. Where, however, dilution of such acomposition seems desirable for a particular use, the dilution may beintegrated with'the method of forming the composition, as follows: Thecaustic phenol and the selected phenolpolarizing agent, in suitablyproportioned quantities, are dissolved, or incorporated, eitherseparately or together, in a quantity of a compatible solvent, ormiscible diluent sufficient to yield a final composition having thedesired phenol concentration. This variant of my novel method may beemployed to advantage when the caustic phenol and the phenol-polarizingagent are both solids at room temperature. The solvent, or misciblediluent, may be non-polar or polar. In fact, if the selectedphenolpolarizing agent is liquid at room temperature, it may, ifdesired, be employed in a dual capacity both as a causticity reducer andas a diluent.

In so far as the individual members of a particular class or genericgroup of polar materials possess characteristics (a), (b) and (c) that Ihave described hereinabove, I have found the following generic classesof compounds to be among those capable of accomplishing broadly theobjects of my invention; including in partic ular a reduction in thecorrosive action of a caustic phenol without a proportionate reductionin other characteristic activities of the phenol: amides; esters;nitriles; oximes;

I have found, additionally, that derivatives or substitution products ofthe foregoing are capable of effecting a reduction in the corrosivenessof a caustic phenol without causing any substantial change in othercharacteristics thereof; and thus of accomplishing the general object ofmy invention (a) when the substituent comprises an anionoid radical; (b)when the substituent corn? prises a cationoid radical-such as halogenoor nitroprovided, that the state of polarization or polarizibility ofthe derivative is preponderantly anionoid; and when the substituentcomprises sulfur. Compounds illustrative of the foregoing group (b) ofpreponderantly anionoid phenol-tempering agents occur in variousexamples given below, more particularly in Example 12. In my use of theterm sulfuretted polar material I intend to include therein substancescontaining a mercapto, a sulfonyl, a thiazolyl, a thio, a thiocarbonyl,a thiocyano or a thiophospho radical.

My use of certain generic designations in the second precedingparagraph, as well as in my claims, is intended to comprehend compoundswhich, unless specifically exceptedsuch as ethers containing the phenoxyradicalcome within ordinary and usual chemical definitions of therespective classes, together with similar, related or analogouscompounds, for example:

Amides include acid amides, anilides and ureas.

Esters include ammonium salts of organic acids; esters of mineral acids;esters containing one or more anionoid radicals other than, or inaddition to, carbonyldioxy; acidulated amines-primary, secondary andtertiary; acidulated alcoholaminesprimary, secondary and tertiary;

Ethers include I In the subjoined list-along with their conventionalchemical formulas or symbolsare examples of polar radicals, anionoid incharacter which are present in substances coming within one or anotherof the classes, genera or groups of polar materials set forth above,which I have found to be capable of accomplishing the general objects ofmy invention. In the su'bjoined list, as well as in Examples 2 to 15,inclusive, ordinary chemical symbols are used in the formulas for thepolar radicals. In the formulas R denotes a hydrocarbon residue.

EFFECTIVE PHENOL-POLARIZING RADICALS cyano (CN), diacyl (OCRCO), epoxy(O.-), furyl i6 (C H O), hydroxyl (OI-I), imino .(NI-I), isonitroso(NOH), keto (0:), mercapto (SH), nitrilo (N), nitrilocarbonyl (NCO),nitroso (NO), oxalyl (OCCO), oxamyl (H NCOCO), phospho (P0 silico (SiOsulfonyl (S0 tetrahydrofuryl (0 1-1 0), thiazolyl (C H NS), thio (S),thiocarbonyl (CS), thiocyano (NCS), thiophospho (PS ureido (HNCONHureylene (HNCONH), unsaturated carbon.

One of the aforenarned phenol-polarizing radicals may be a component ofa larger radical; for example, carbonyl is a component of acyl, ofacyloxy, of aldo, of carbonyldioxy, and of other polar radicals.Nevertheless, for the purposeof this invention, each of the aforelistedeffective. phenol-polarizing radicals is to be considered in itsentirety and as a different kind of radical from each of the others. Apolar compound, which is an effective phenol-tempering agent, maycontain unsaturated carbon in its molecular structure. Such unsaturatedcarbon is embraced within the general terms polar radical and anionoidradical; audit may contribute somewhat to the phenol-tempering capacityof a compound which additionally contains another and different kind ofpolar radical. Standing alone in a hydrocarbon, however-as illustratedby pinene and the xylenes in Example 1 above-unsaturated carbon exertsan anionoid action which is insufiicient to render the hydrocarbonsuitable for use as a .sole. phenol-tempering agent in the practice ofmy invention. Consequently, I have employed one or more control mixturesof caustic phenols and substantially nonpolar hydrocarbons, similar tothose illustrated in Example 1, as criteria for determining thephenoltempering capacity of a polar material under test,'when formedintoa substantially homogeneous physical mixture with a given causticphenol-where the latter, and its proportion in the test mixture, wherethe same as in the control mixture or mixtures.

In Examples 2 to 15, inclusive, are set out illustrative results takenfrom many hundreds of skin reaction tests that 'I have made on as manydifferent compositions comprising a caustic phenol and aphenol-polarizing agent. In order to present these data as concisely aspossible I shall use code symbols as follows: 7

Representative caustic phenols that I have tested are carbolic acid (I),tricresol (II), o-chlorophenol (III), pchlorophenol (IV), and2,4-dichlorophenol (V). In the examples below the phenol (or phenols)tested with a stated polar material appears'under its symbol in Romannumerals in parentheses following the name of the polar material. Itwill be observed that in many instances more than one species of causticphenol was tested with the same phenol-polarizing agent. Unlessindicated otherwise, the ratio of polar material to caustic phenol was1:1; that is, the mixture, as originally made up, consisted of 50percent of the phenol and 50 percent of the polar material. In certaininstances, however, shown by the notation sat, some of the polarmaterial separated from a liquid mixture which was in equilibriumtherewith. In such a case the skin test was made with the liquid; thephenol, consequently, comprising a major fraction of the liquid.

For convenience of comparison, the various polar materials have been putinto one or another of four cate-v gories-namely, A, B, C, andDrepresenting diminishing grades of effectiveness as phenol-polarizingagents. The mixtures classed in group A evidenced. no caustic action ona fifteen minute contact with the skin. The mixture in group B eliciteda moderate grade of caustic reaction--i.e., beginning burning orincomplete analgesia-in 11 to 15 minutes; those in group- C a like gradeof reaction in 6 to 10 minutes, and those ingroup D a similar reactionin 2 to 5 minutes.

In a few instances, as already has been pointed out, no caustic efiectwas observed until a major portion of the polar material hadvolatilized. Those cases are indicated by thexnotationfevap. 1

At the head of each of Examples 2 to 15, inclusive, there is aparenthetic note listing the polarradicalsto be foundtin one or anotherof the specific polar compounds tcsted-which have rendered the compoundssuitable as phenol-tempering agents. Unless otherwise indicated, suchpolar radicals are anionoid in character. Those skilled in the callingwill recognize which one or more of the polar radicals thusparenthesized is present in a given polar material.

Example 2.Alcohols (monohydric)* Example 3.-Alcohols (dihydric)* Example4.-Aldehydes* I Example 5.Amides, includingacid amides, anilides andureas. (Polar radicals: Acyl, acylamino acyIiminO, carbamyl,oarbonylimino, nitrilocarbonyl, ureido, and ureylene.)

A. Acetamide (I); acetanilide (I-sat.); acetoacetanilide (I, II, IV);p-acetophenetide (I-sat.; II-sat.; III-sat); benzamide (I-solid);N-butylauramide (I, HI); butyl urea (I); caproamide (I); caproanilide(I-sat.; V-sat.); dibutyl cyanamide (I); N,N-di-n-butyllauramide (IV);N,N-diethylacetamide (I); N,N'-diethyl-N,N'-diphenylurea (I); heptamide(I-sat; V-sat.); phenylacetamide (I- sat.); Z-phenylbutyramide (I, II);o-toluamide (I-sat.; Ii-sat.; V-paste); urea (III-solid) B. Benzamide(IV-sat); N,N-di-n-butyllauramide (I).

C. p-Toluamide (I-soft mass).

D. Octadecanamide (I-paste); palmitamide (I-solid).

-Exa'mple 6.Esters, including esters of mineral acids, ammonium salts oforganic acids, esters containing one or more anionoid radicals otherthan carbonyldioxy, acidulated amines-primary, secondary and tertiaryandacidulated alcoholaminesprimary, secondary and tertiary. (Polarradicals: Acyl, amino, carbamyl, carbonyl, carbonyldioxy, cyano, diacyl,furyl, hydroxyl, imino, nitrilo, oxalyl, oxamyl, phospho, *,unsaturatedcarbon.)

Represenative examples of polar materials which I have found to besuitable for the practice of my invention and which I term esters, areset forth, together with the results of causticity-reduction tests, insubdivisions 6a, 6b, and 6c of the present example. In subdivision 6aare included examples of esters other than examples of acidulated aminesand acidulated alcohol amines; the latter two groups being listed,respectively, under subdivisions 6b and 60.

A. ammonium acetate (1); isoamyl carbamate (I, V);diacetylethylenediamine (I- sat.; II-sat.; V-sat.); ethyl carbamate (I,H, III); ethyl cyanoacetate (I); ethyl oxanilate (I, II); i ii llib-Acidulated amines Amines and alcoholamines constitute polarmaterials which, by reason of their basicity, form reaction productswith caustic phenols. Such basic substances consequently are notsuitable, per se, for the practice of my invention. Salts of amines andof alcoholamines, however, which are substantially neutral, or evensomewhat acid in reaction, are adapted in general to form with causticphenols physical mixtures which constitute typical embodiments of myinvention.

In the next succeeding five paragraphs hereof I shall use the term amine(or amines") to include the alcoholamines.

The salts of amines which are adapted for the practice of my invention Ipreferably prepare by reacting a quantity of a given amine with anamount of a selected acid sufficient to yield a substantially neutralproduct. In

order, however, to prevent any appreciable chemical reaction between anyfree amine and the later added caustic phenol, 'I prefer to carry theneutralization of the amine slightly to the acid side of neutrality,i.e., to form a product which is acid to litmus paper; the reactionbeing tested on a solution of a trace of the product in a few drops ofdistilled water.

7 In the case of an aliphatic or an alicyclic amine a suitable degree ofneutralization ordinarily may be effected by reacting equivalent weightsof the amine and of the acid. Nevertheless, as I have said, I prefer tocarry the acidification to a slight acidity. In some of the mixtures setforth in the present subdivision, as well as in subdivision 6c of thepresent example, it will be observed that the amine salt has been formedwith an excess of acid. In consequence, I prefer to employ the termsacidulated amine and acidulated alcoholaminc instead of amine sal andalcoholamine salt; respectively. Because of the low basicity, however,of aromatic amines in comparison with aliphatic and alicyclic amines, Iprefer, in the case of an aromatic amine, to react therewith a quantityof selected acid not substantially greater than is necessary to form aproduct that is faintly acid to litmus paper. This comes within my termsubstantially neutral."

Since my preferred criterion of suitable acidification of an amine isbased upon the reaction of the product toward an indicator rather thanupon the use of equivalent weights of the reactants, I prefer to employthe term acidulated amine rather than amine salt.

I include also, in my use of the terms acidulated amines and acidulatedalcoholamines," nitrogenous compounds, of originally basic character,which have been acylated to an extent that renders them substantiallyneutral in reaction. An example of such an acylated base isdiacetylethylenediamine. For present purposes, however, this compoundhas been included in group 6a.

In forming an acidulated amine, I preferably employ a lower fatty acidsuch as acetic acid or propionic acid. Nevertheless, I have found thatany acid is suitable therefor when the resulting product is capable offorming'a substantially homogeneous physical mixture with an equal ormajor quantity--preferably not more than five times its weightof acaustic phenol. Examples of acids, other than acetic and propionicacids, that I have used to form salts of amines and of alcoholamines,are: Adipic; benzilic; benzoic; cinnamic; cyclohexanecarboxylic; diglycolic; ethylphosphoric; furoic; glycolic; heptylic; hydrocinnamic;lauric; levulinic; malonic; myristic; naphthenic acids (practicalgrade); oleic; oxalic; phenylacetic; salicylic; sebacic; stearic;d-tartaric; and undecylenic.

All of the substantially neutral, or somewhat acid, salts of amineand/or of alcoholamines, that I have formed with the foregoing acids, Ihave found to be efiective as causticity-reducing agents for causticphenols.

In forming an acidulated amine or alcoholamine I may employ an acidanhydride instead of an acid. Examples of acid anhydrides that I haveemployed to form salts of amines and/ or of alcoholamines are: Benzoic;Z-furoic; heptylic; phthalic; propionic; and succinic.

All of the acidulated amines and alcoholamines that I have formed withthe foregoing acid anhydrides, I have found to be effective ascausticity-reducing agents for caustic phenols.

The following representative instances under the present subdivision bof Example 6 (Esters) serve to illustrate (1) the formation ofacidulated amines and the subsequent formation of physical mixtures ofcaustic phenols therewith; and (2) the results of tests showing thegeneral suitability of such acidulated amines for use in the practice ofmy invention.

.In subdivision c of the present Example 6 are set out, in similarfashion, data on representative examples of acidulated alcoholamines andof physical mixtures thereof with caustic phenols.

13 The code letters, A, B, C, and D, employed inearlier examples toindicate the relative effectiveness of a given polar material as acausticity-reducing agent, will be used with like significance insubdivisions 6b and 6c. The code letter, however, will be placed at theend of the formula for a given mixture.

6b.-Acidula'ted amines SERIES 1.AMINES ACIDULATED \VITH PROPIONIC ACID1.2 parts 4-amino-l,3-dimethylbenzene plus 0.8 part propionic acid; plus2.0 parts tricresol; A.

(b) 1.4 parts o-aminodiphenyl plus 0.7 part propionic acid; plus 2.1parts tricresol; D.

(c) 1.4 parts p-aminodiphenyl plus 0.7 part propionic acid; plus 2.1parts tricresol; C.

(d) 1.1 parts mouoamyla-mine plus 1.0 part propionic acid; plus 2.1parts tricresol; A.

(e) 1.2 parts o-anisidine plus 0.8 part propionic acid;

plus 2.0 parts tricresol; B.

(i) 1.5 parts benzoyl-l-naphthylamine plus 0.5 part propionic acid; plus2.0 parts tricresol; D.

(g) 1.5 parts benzylamine plus 1.0 part propionic acid;

plus 2.5 parts carbolic acid; A.

(h) 1.4 parts benzyl-o-toluidine plus 0.6 part propionic acid; plus 2.0parts tricresol; C.

(i) 1.8 parts N-(mono-n-) butylaniline plus 0.3 palt propionic acid;plus 2.1 parts carbolic acid; C.

(,1) 1.0 part cyclohexylamine plus 1.3 parts propionic acid; plus 2.3parts carbolic acid; A.

(k) 1.0 part 2,4-diaminotoluene plus 1.2 parts propionic acid; plus 2.2parts tricresol; A.

(l) 1.0 part diamylamine plus 1.0 part propionic acid;

plus 2.0 parts carbolic acid; A.

(m) 2.3 parts dibenzylamine plus 1.2 parts propionic acid; plus 3.5parts carbolic acid; A.

(n) 1.8 parts N,N-di-n-butylaniline plus 0.2 part propionic acid; plus2.0 parts carbolic acid; B.

(o) 2.5 parts dicyclohexylamine plus 1.0 part propionic acid; plus 3.5parts carbolic acid; A.

(p) 1.1 parts N,N-diethylcyclohexylamine plus 1.4 parts propionic acid;plus 2.5 parts carbolic acid; A.

(q) 1.0 part diethylenetriamine plus 1.5 parts propionic acid; plus 2.5parts carbolic acid; A.

(r) 1.4 parts diethyl-o-toluidine plus 0.7 part propionic acid; plus 2.1parts tricresol; A.

(s) 2.0 parts dimethylaniline plus 0.3 part propionic acid; plus 2.3parts carbolic acid; A.

(t) 0.6 part ethylenediamine plus 1.7 parts propionic acid; plus 2.3parts carbolic acid; A.

(u) 1.0 part heptylamine plus 1.5 parts propionic acid;

plus 2.5 parts carbolic acid; A.

(v) 0.65 part hydrobenzamide plus 0.35 part propionic acid; plus 1.0part tricresol; A.

(w) 1.2 parts methylaniline plus 0.9 part propionic acid;

plus 2.1 parts tricresol; B.

(x) 1.0 part morpholine plus 1.0 part propionic acid;

plus 2.0 parts carbolic acid; A.

(y) 1.3 parts l-naphthylamine plus 0.8 part propionic acid; plus 2.1parts tricresol; C.

(z) 1.3 parts p-phenetidine plus 0.9 part propionic acid;

plus 2.2 parts tricresol; A.

(an) 1.0 part p-phenylenediamine plus 1.5 parts propionic acid; plus 2.5parts tricresol; C.

(bb) 1.6 parts phenethylamine plus 1.0 part propionic acid; plus 2.6parts carbolic acid; A.

(cc) 1.3 parts propylenediamine plus 3.5 parts propionic acid; plus 4.8parts carbolic acid; A.

(dd) 1.2 parts pseudocumidine plus 0.8 part propionic acid; plus 2.0parts tricresol; B.

(ca) 1.2 parts o-tolidine plus 0.9 part propionic acid;

plus 2.1 parts tricresol; B.

(ff) 1.2 parts o-toluidine plus 0.9 part propionic acid;

plus 2.1 parts tricresol; B.

plus 2.1 parts tricresol; B.

(izh) 2.0 parts tributylamine plus 1.5 parts propionic acid; plus 3.5parts carbolic acid; A.

(ii) 1.0 part triethylenetetramine plus 1.5 parts propicnic acid; plus2.5 parts carbolic acid; A.

SERIES 2.-AMINES ACIDULATED WITH ACIDS OTHER THAN PROPIONIC ACID (a)0.55 part o-aminodiphenyl plus 0.45 part cyclohexanecarboxylic acid;plus 1.0 part 2,4-dichlorophenol; C.

(b) 0.55 part monoamylamine plus 0.45 part oxalic acid;

plus 1.0 part 2,4-dichlorophenol; D.

(c) 0.28 part aniline plus 0.72 part myristic acid; plus 1.0 parto-chlorophenol; D.

(d) 0.55 part benzylamine plus 0.45 part glycolic acid;

plus 1.0 part p-chlorophenol; B.

(e) 0.44 part cyclohexylamine plus 0.56 part benzoic acid; plus 1.0 parto-chlorophenol; B.

( 1.0 part cyclohexylamine plus 1.5 parts ethylphosphoric acid; plus 2.5parts carbolic acid; A.

(g) 1 .0 part cyclohexylarnine plus 1.5 parts levulinic acid;

plus 2.5 parts carbolic acid; A.

(h) 1.0 part cyclohexylamine plus 2.3 parts naphthenic acids (practicalgrade); plus 3.3 parts carbolic acid; A.

(i) 2.0 parts cyclohexylamine plus 9.5 parts oleic acid;

plus 11.5 parts carbolic acid; C.

(i) 1.2 parts diamylamine plus 0.8 part benzilic acid; plus 2.0 partstricresol; A.

(k) 1.1 parts diamylamine plus 0.9 part benzoic acid;

plus 2.0 parts tricresol; A.

(l) 1.0 part diamylamine plus 1.1 parts cinnamic acid;

(0) 1.2 parts diamylamine plus 0.9 part furoic acid;

plus 2.1 parts tricresol; A.

(p) 1.3 parts diamylamine plus 1.2 parts of glycolic acid;

plus 2.5 parts tricresol; A.

(q) 1.0 part diamylamine plus 1.0 part hydrocinnamic acid; plus 2.0parts tricresol; A.

(r) 1.5 parts diamylamine plus 0.9 part malonic acid;

plus 2.4 parts tricresol; A.

(s) 0.5 part diamylarnine plus 1.5 parts myristic acid;

plus 2.0 parts tricresol; C.

(t) 1.0 part diamylamine plus 3.5 parts oleic acid; plus 4.5 partscarbolic acid; C.

(u) 1.4 parts diamylamine plus 0.6 part oxalic acid;

plus 2.0 parts tricresol; A.

(v) 1.0 part diamylamine plus 1.0 part phenylacetic acid;

plus 2.0 parts tricresol; A.

(w) 0.6 part diamylamine plus 0.4 part sebacic acid;

plus 1.0 part o-chlorophenol; A.

(x) 1.0 part diamylamine plus 1.0 part d-tartaric acid;

plus 2.0 parts tricresol; A.

(y) 0.6 part dibenzylamine plus 0.4 part furoic acid;

plus 1.0 part 2,4-dichlorophenol (sat); A.

(z) 0.44 part dicyclohexylamine plus 0.56 part benzilic acid; plus 1.0part p-chlorophenol; B.

(aa) 0.5 part N,N-diethylcyclohexylamine plus 0.7 part salicylic acid;plus 1.2 parts 2,4-dichl0rophenol; A. (bb) 0.4 partN,N-diethylcyclohexylamine plus 0.6 part salicylic acid; plus 1.0 parttricresol; A.

(00) 0.58 part diphenylamine plus 0.42 par-t levulinic 38) 0.7 partl-naphthylamine plus 0.3 part ethylpho si phoric acid; plus 1.0 partp-chlorophenol; C.

(hi1) 0.25 part m-phenylcnediamine plus 0.75 part-cinnamic acid; plus1.0 part tricrc-sol (sat.); E.

(ii) 0.26 part p-plicnylcncdiamiuc plus 0.74 part oleic acid; plus 1.0part 2,4-dichlorcphenol (sat.); B.

(ii) 0.42 part o-toluidinc plus 058 part phenylacetic acid; plus 1.0part 2,4-dichlorophcnol; A.

(klc) 0.7 part tributylamine plus 0.3 part adipic acid;

plus 1.0 part p-chlorophenol; A.

(mm) 1.0 part tributylamine plus 2.0 parts olcic acid;

plus 3.0 parts carbolic acid; B. Y 7

SERIES 3.AMINES ACIDULATED WITH ACID ANHYDRIDES (a) 1.1 partsdiamylaminc plus 0.9 part benzoic anhy- 6c.-Acidulated alcoholaminesspams 1.--ALCOHOLAMINES ACIDULATED WITH PROPIONIC ACID (u) 0.45 partl-aminoethanol plus 0.55 part propionic acid; plus 1.0 partc-chlorophcnol; A.

(b) 1.2 parts Z-aminc-Z-methyl-l,3-prcpanediol plus 0.9

part propionic acid; plus 2.1 parts tricrcsol; A.

(c) 1.0 part 2-amino-2-methyl-l-propanol plus 1.0 part propion-ic acid;plus 2.0 parts carbolic acid; A.

(d) 1.4 parts butyldictiianolaminc plus 0.9 part prcpionic acid; plus2.3 pans tricresol; A.

(e) 1.2 parts hutylmonoethanolarninc plus 0.8 part propionic acid; plus2.0 parts tricresol; A. (f) 1.0 part diethanolaminc plus 1.0 partpropionic acid;

plus 2.0 parts carbolic acid; A. r (g) 1.0 part 2-diethylaminocthanolplus 1.0 part propionic acid; plus 2.0 parts carbolic acid; A.

(h) 1.0 part di-iso-propanolamine plus 0.5 part propionic acid; plus 1.5parts carbolic acid; A.

(i) 0.6 part cthyldicthanolamine plus 0.4 part propionic acid; plus 1.0part tricresol; A.

(j) 4.7 parts 2-hydroxycthylaniline plus 0.5 part propionic acid; plus5.2 parts carbolic acid; B.

(k) 1.2 parts hydroxyethylethylcnediaminc plus 1.7 parts propionic acid;plus 2.9 parts carbolic acid; A. (l) 1.3 parts2-hydroxyethyl-p-t0luidine plus 0.7 part propionic acid; plus 2.0 partstricresol; D. (m) 1.6 parts tni-iso-propanolam-ine plus 1.0 partpropicnic acid; plus 2.6 parts carbolic acid; A.

SERIES 2.--ALCOHOLAMINES ACIDULATED WITH ACIDS OTHER THAN PROPIONIC ACID(a) 1.3 parts 2-aminc-2-methyl-l-propanol plus 2.5 partsethyl-phosphoric acid; plus 3.8 parts carbolic acid; A.

(b) 1.0 pait 2-amino-2-methyl-l-propanol plus 6.0 parts naphthenic acids(practical grade); plus 7.0 parts carbolic acid; C.

(c) 1.0 part 2-amino 2-mcthyl-l-propanol plus 5.0 parts oleic acid; plus6.0 parts carbolic acid; B.

(d) 0.5 part butyldiethanolamine plus 0.5 part hydrocinnamic acid; plus1.0 part o-chlorophenol; A.

(e) 0.65 part butylmouoethanolamine plus 0.35 part malonic acid; plusl.0 part p-chlorophenol; A.

(f) 2.0 parts diethanolarnine plus 3.7 parts ethylphosphoric acid; plus5.7 parts carbolic acid; A.

(g) 2.0 parts dicthanolamine plus 3.3 parts levulinic acid;

plus 5.3 parts carbolic acid; A.

(h) 0.63 pait 'dicthanolaminc plus 0.37 part maleic acid;

plus 1.0 part 2,4-dichlorophenol; A.

(i) 1.0 part dicthanolaminc plus- 3.5 parts naphthenic acids (practicalgrade); plus 4.5 parts carbolic acid; A.

(i) 1.0 part dicthanolaminc plus 5.0 parts cleic acid;

plus 6.0 parts cai'bolic acid; C.

(k) 0.42 part 2-dicthylamin0ethanol plus 0.58 part cinnamic acid; plus1.0 part 2,4-dichlorophenol; A.

(l) 1.0 part tricthanolamine plus 2.2 parts benzilic acid;

plus 3.2 parts tricresol; A.

(m) 1.0 part triethanolamine plus 1.3 parts benzoic acid;

plus 2.3 parts tricresol; A.

(n) 1.0 part triethanolaminc plus 1.7 parts cinnamic acid;

plus 2.7 parts tricresol; A.

(0) 0.8 part triethanolaminc plus 1.2 parts cyclohexanc carboxylic acid;plus 2.0 parts tricresol; A.

(p) 1.0 part triethanolamine plus 1.0 part diglycolic acid; plus 2.0parts tricresol; A.

(q) 0.68 pal: triethanolamine plus 0.32 part diglycolic acid; plus 1.0part o-cl1lorophenol; A.

(r) 0.7 part triethanolamine plus 1.4 parts furoic acid;

plus 2.1 parts tricrcsol; A.

(s) 1.0 part triethauolamine plus 1.0 part glycolic acid;

plus 2.0 parts tricrcsol; A.

(t) 0.5 part tricthanolamine plus 1.7 part heptylic acid;

plus 2.2 parts tricresol; A.

(u) 0.7 part triethanolamine plus 1.3 parts hydrocin' namic acid; plus2.0 parts tricresol; A.

(v) 0.5 part triethanolamine plus 1.5 parts lauric acid;

plus 2.0 parts tricrescl; A.

(w) 1.5 parts tricthanolamine plus 1.0 part malonic acid;

plus 2.5 parts tricresol; A.

(x) 2.0 parts tricthanolamine plus 4.3 parts naphthenic acids (practicalgrade); plus 6.3 parts carbolic acid; A.

(y) 1.0 part triethanolamine plus 1.0 part oxalic acid;

plus 2.0 parts tricresol; C.

(Z) 1.0 part triethanolamine plus 1.3 parts pheuylacctic acid; plus 2.3parts tricresol; A.

(ca) 0.5 part triethanolamine plus 2.0 parts stearic acid;

plus 2.5 parts tricrcsol (paste); C.

(bb) 1.0 part triethanolamine plus 1.0 part d-tartaric acid; plus 2.0parts tricresol; A.

(cc) 1.0 part triethanolamine plus 4.0 parts undecylenic acid; plus 5.0parts tricresol; A.

SERIES 3.ALCOHOLAMINES ACIDULATED WITH ACID ANHYDRIDES (a) 0.42 partZ-diethylaminoethanol plus 0.58 part phthalic anhydride; plus 1.0 part2,4-dichlorophenol; A.

(b) 0.9 part triethanolamine plus 1.2 parts benzoic anhydride; plus 2.1parts tricresol; A.

(c) 0.55 part triethanolamine plus 0.45 part benzoic anhydride; plus 1.0part o-chlorophen'ol; A.

(d) 1.0 part triethanolaminc plus 2.4 parts 2-furcic anhydride; plus 3.4parts tricresol; A.

(e) 0.6 part triethanolamine plus 1.5 parts heptylic anhydride; plus 2.1parts tricrescl; A.

(f) 1.0 part triethanolamine plus 1.0 part phthalic anhydridc; plus 2.0parts tricresol; A.

(g) 1.0 part triethanolamine plus 1.0 part propionic anhydridc; plus 2.0parts tricresol; A.

(h) 1.2 partstricthanolamine plus 0.8 part succinic anhydride; plus 2.0parts tricresol; A.

17 nitrogen linkage. (Polar radicals: Azoxy, isonitroso, nitroso.)

A. Acetone oxime (I, II); ethyl-N-nitroso-N-methylctltlrbamate (I, II);heptaldoxime (HI); nitrosobenzene B. Cyclohexanone oxime (I, IV).

C. Azoxybenzene (I); nitrosobenzene (I); isonitrosomethyl hexyl ketone(I, IV).

D. Isonitrosomethyl hexyl ketone (II).

Example 12.Polar compounds containing both anionoid and cation-oidradicals. (Polar radicals-anionoid: acyl, acylimino, carbonyl,carbonyldioxy, hydroxyl, sulfonyl, unsaturated carbon; cationoid:halogeno, nitro.)

A. Acetoacet-2,5-dichloranilide (I); o-chloroacetanilide (I);2-nitro-2-ethyl-1,3-propanediol (I, H); 2-nitro-2- methyl-l-propanol(II).

B. o-Chloroacetanilide (III); l-nitronaphthalene (II).

C. o-nitro-diphenyl (I, III); 2-nitro-2-ethyl-1,3- propanediol (III);2-nitro-2-methyl-1-propanol (I, IV).

D. 2-nitro 1 butanol (I, II, V); 2-nitro-2- methy1-1,3-propanedio1(I-sat.; II-sat.); 1-nitronaphthalene (I).

Example 13.Sulfuretted polar compounds. (Polar radicals: Mercapto,(thiazolyl, thiocyano, a 1: j

A. Benzothiazole (I, V); zothiazole (I, H);

C. Benzylthiocyanate (I);

Example 14.-Organic acid anhydrides* Example 15.Acids-* In the foregoingillustrative Examples 2 to 15, inclusive, each composition contained apolar material which either completely inhibited the corrosive action ofa typically caustic phenol, or which delayed the onset of caustic efiectfor a period of time which was upwards of twice the time of onset of alike efiect elicited by a control mixture of the same phenol in asubstantially nonpolar hydrocarbon solvent or diluent of the typeillustrated in Example 1.

Moreover, each of the polar materials set out in Examples 2 to 15,inclusive, possesses characteristics (a), (b) and (c) which, as alreadystated, are requisites of a phenol-polarizing agent suitable for use inthe practice of my invention; each of said polar materials thusconstituting a representative species of phenol-polarizing agent comingwithin one or another of the generic classes of polar materials definedby the respective captions that identify Examples 2 to 15, inclusive. AsI already have stated hereinabove, all members of these generic classesof polar materials come within the scope of my invention in so far asany member thereof possesses characteristics (a), (b) and (c) and is nototherwise excluded by reason of any specific limitation that I may haveset forth herein.

Example 16.-Tests of mixtures of carbolic acid with two compatible polarmaterials belonging to difierent classes of compounds.

Thirty-six mixtures were made up, each containing 50 percent of carbolicacid; the remainder of each mixture, respectively, being divided equallybetween two difierent compounds selected seriatim from the followingrepresentative classes of polar materials: Acid amides, acidulatedalcoholarnines, aldehydes, anilides, esters, ethers, ketones, nitrilesand sulfones. The specific representatives of these classes were,respectively: Acetamide; triethanolamine-1.3 parts, neutralized tolitmus with propionic acid-0.7 part; aldol; acetoacetanilide; methylphthalate; amyl ether; mesityl oxide; octadecanenitrile and sulfonal.

The 36 mixtures were made up so that in no two thereof was thecombination of polar radicals the same. The polar radicals were: Acyl;acylamino; aldo; alkoxy; carbonyl; carbonyldioxy; carbonylimino; cyano;hydroxyl; nitrilo and sultonyl.

. 2-methylmercaptoben- None of the 36 mixtures--each, as aforesaid,containing 50 percent of carbolic acid--exhibited any caustic activitywhen tested on the skin for 15 minutes. That is, all of the mixtureswere classifiable in group A, as that category has been employed inpreceding examples.

In order to conform to the requisite characteristic (0) of a polarmaterial for use in the practice of my invention,- the minimal eiiectiveratio of a suitable polar material to a caustic phenol may not be higherthan 1:1 I have found many phenol-polarizing agents, however, each ofwhich is adapted to temper two or more times its: weight of a causticphenol.

In the course of determining the minimal operative ratios ofrepresentative species of the more highly effective phenol-polarizingagents-more particularly those classed as A in Examples 2 to 13,inclusiveI have found that in many instances this minimal operativeratio, as determined by the skin reaction test above described,substantially coincides with that ratio which just, suflices to preventthe segregation, within the mixture, of any appreciable proportion ofthe phenol as a separate phase. There are various tests known to the artfor detecting such a segregation. Since the majority of caustic phenols,that come within the scope of my invention, crystallize, when pure, attemperatures higher than ordinary room temperatures, I have found it atime-saving and convenient procedure to determine, first, by trial, thatratio of a polar material to a caustic phenol which just sufiices toprevent any crystallization of the phenol from its mixture with thepolar material when the mixture either is allowed to stand for some timeat room temperature in a closed container; or, preferably, is seededwith a crystal of the phenol. In effect, a mixture thus formed comprisesa polar material which is substantially saturated with the phenol.The'causticity-reducing capacity of the polar material in such a mixtureI may then determine by the skin reaction test above described.

In Example 17 are set forth the results of skin reaction tests made oncompositions embodying my invention; each consisting of a representativephenol-polarizing agent in admixture with two or more times its weightof crystalline carbolic acid, most of the compositions beingsubstantially saturated therewith. Carbolic acid was chosen for thisseries of compositions because it is the most sharply corrosive of thecaustic phenols.

In Example 17 the second member of each ratio denotes the number ofparts of carbolic acid in admixture with unit part of eachphenol-polarizing agent listed after a given ratio; while the percentagefigures in parentheses denote the proportions of phenol-polarizingagents that are present. The parenthetic B, C or D following each listedpolar material carries with it the same connotation that is attached toit in Examples 2 to 15, inclusive.

Example 17.

1:9 (10%)Acetamide (D) 1:5 (16.7%) *;-benzothiazole (D);

1:4 (20%)-p-Acetophenetide (D); diacetylethylenediamine (B); 7

1:3 (2S%)Acetoacetanilide (D); triethanolamine, acidulated as in Example16 (D).

1:2 (33.3%)- octadecanenitiile (D);

Having reference to the call in my claims for a mixture of a polarmaterial and a caustic phenol, and more particularly for an amount ofthe polar material sufficient to reduce the causticity of the phenol, Iintend the phrase just quoted to mean that the ratio of polar materialto the caustic phenol shall be at or above the minimum that justsutlices to effect a distinct reduction in the corrosiveness of thephenol, as evidenced by the results-either qualitative or quantitativeor both-obtained in comparative skin reaction tests of theaforementioned mixture and of a homogeneous control mixture consistingof a like proportion of the same phenol a 19 and a substantiallynonpolar hydrocarbon which is liquid at ordinary temperatures and is ofthe character illustrated in Example 1.

I have tested representative compositions embodying my invention, eachcomposition containing at least 50 percent of a. caustic phenol,ordinarily carbolic acid; and I have found such compositions to behighly effective as insecticidal sprays, as general disinfectants and asgermicidal, fungicidal and insecticidal agents in such infections andinfestations of the skin as pimples, incipient boils, ringworm, mangeand pediculosis. a

My conception of the mechanism of reduction in corrosiveness of acaustic phenol by a suitable polar material stems from the recentextension of electron theory into the field of organic chemistry. Instating my conception I desire to set forth what appears to me to be arational scientific explanation of my broad discovery. I do not confinemyself, however, to that explanation, nor do I intend thereby to limitin any manner or degree the scope of the invention herein described andclaimed.

It now is recognized that a chemical reaction-in the conventional senseof the formation of one or more products difiering in molecularstructure from the reactants-involves the operation of valence forcesleading to exchange of electrons and the formation of chemical bondsbetween electron-seeking and electron-donating centers or zones withinthe molecules of the respective reactants. The formation of distinctreaction products, however, may be conditioned upon one or morecircumstances such as the special chemical characters of the reactants,the development of an adequate electron density at the sites of reactionin electron-donating molecules, and environmental factors such asfavorable solvent media, auxiliary activating agencies such as heat andpressure, catalysts, et cetera.

There are, however, attraction forces, operative between unlikemolecules, which are not as strong as the valence forces aforementioned,namely, intermolecular forces insufiicient, per se, to lead to electronexchanges and the formation of reaction products, but sufficient toresult in the formation of loose physical complexes. Thus, polarmolecules of unlike species may orient each other in much the samemanner as two freely movable small bar magnets when brought within theirmutual spheres of influence. The result is the formation of loosephysical complexes which do not obey the laws of combining proportionsand of multiple proportions. In such orientation complexes unlikemolecules are held together by electrostatic attraction between positivepoles of one molecular species and negative poles of another. The degreeof electroaffinity between the unlike molecules making up such physicalcomplexes depends principally upon two independent variables, namely,(1) the the same phenol when mixed in like proportion with'asubstantially nonpolar hydrocarbon solvent.

In order to explain the germicidal and fungicidal character oforientation complexes embodying my inven: tion, I assume thatsuchcomplexes break up or dissociate in contact with highly polar freeor solvent; water molecules leaving the phenol molecules in a statewherein they are conditioned for their typical toxic and disinfectantaction by a favorable solvent medium, namely water. ,Incidentally, it isbecause water is one of the polar materials which, other than by anyeffect as a diluent, does not reduce the corrosiveness of a causticphenol, that compositions embodying my invention preferably aresubstantially water-free.

states of polarization of the unlike molecules and (2) their respectivepolarizabilities.

The-foregoing alfords, I believe, the basis for a working theory of themechanism of the tempering of a caustic phenol by a suitable polarmaterial in the practice of my invention. I postulate the formation ofphysical complexes of caustic phenols and phenol-tempering agentsthrough the mechanism of orientation polarization that I have justdescribed. On this postulate is based my preferred use of the termphenol-polarizing agent. Since-as is shown by the many examples that Ihave given-phenol-tempering capacity is a function of anionoid radicals,and since the phenyl group is electronattracting in character, I assumethat in an orientation complex of a caustic phenol andaphenol-polarizing agent, the phenyl radical or residue in the phenoland the anionoid portion of the phenol-polarizing molecule constitutethe zones of electrostatic attraction and of closest proximitytherebetween. According to my theory, then, the phenol in an orientationcomplex with a phenol polarizing agent exhibits less afinity for waterthan does In a composition embodying my invention the apparently.paradoxical combination of high germicidal and fungicidal activitytoward microorganisms on or in the skin, with the absence of causticeffect upon the skin itself, may be explained in part by ther'elativelylow content of unbound water in the outermost layer of theepidermis; whereas microorganisms which may be invading the skin have ahigh solvent water content character-' istic of living protoplasm. Avery important circumstance, moreover, is the great surface extension,relative to their individual masses, in microorganisms. Further more, mypreferred compositions are those which com' prise fifty percent or'moreof a caustic phenol; so that the concentration gradient of the phenolbetween such a composition and a group of microorganisms is very high,and the destruction of the latter correspondingly p l Having referenceto all of the examples set forth hereinabove, I desire it to beunderstood that they-as well as all specific compounds, substances, ormaterials, and all quantities, parts, proportions or ratios giventherein-are intended to be illustrative only and in no sense limitativeof'my invention other than as the same is defined in the accompanyingclaims.

I claim:

l. A substantially water-free, phenolic, gcrmicidal composition that isadapted as such for direct local application, said compositioncomprising a highly caustic phenol in substantially homogeneous physicaladmixture with a nitrogenous polar material whose molecular structure isrendered preponderantly anionoid in character by the presence therein ofan effective number of electron-donating polar groups; said polarmaterial being further characterized (a) by being chemically compatiblewith the caustic phenol, and (b) by being capable of forming asubstantially homogeneous physical system with more than its weight ofthe caustic phenol; the polar material in said physical system--whensaid system, so formed, is applied to a substantially dry, cutaneoussurfacecausing the phenol therein to exhibit a delay in the time ofonset of its caustic effect of at least percent beyond the time of onsetof caustic eifect of a control mixture containing the same phenol in thesame proportion by weight as in said physical system, but with saidpolar material being substituted in the control mixture by asubstantially nonpolar hydrocarbon of the class consisting ofcyclohexane, pinene, p-xylene and a mixture of isomeric xylenes; saidpolar material being an acidulated amine; said composition containingthe caustic phenol in an effective germicidal concentration; and saidacidulated amine being present in the composition in an amountsufficient to reduce the causticity of the phenol withoutproportionately reducing its germicidal power.

2. A substantially water-free, phenolic, germicidal composition that isadapted as such for direct local application, said compositioncomprising a highly caustic phenol in substantially homogeneous physicaladmixture with a nitrogenous polar material whose molecular structure isrendered preponderantly anionoid in character by the presence therein ofan effective number of electrondonat ing polar groups; said polarmaterial. being further char- 21 acterized (a) by being chemicallycompatible with the caustic phenol, and (b) by being capable of forminga substantially homogeneous physical system with more than its weight ofthe caustic phenol; the polar material in said physical system-when saidsystem, so formed, is applied to a substantially dry, cutaneoussurfacecausing the phenol therein to exhibit a delay in the time ofonset of its caustic efiect of at least 100 percent beyond the time ofonset of caustic effect of a control mixture containing the same phenolin the same proportion by weight as in said physical system, but withsaid polar material being substituted in the control mixture by asubstantially nonpolar hydrocarbon of the class consisting ofcyclohexane, pinene, p-xylene and a mixture of isomeric xylenes; saidpolar material being an acidulated alcoholamine; said compositioncontaining the caustic phenol in an efiective germicidal concentration;and said acidulated alcoholamine being present in the composition in anamount 2,347,983 Backoif May 2, 1944 FOREIGN PATENTS 609,164 GermanyFeb. 8, 1935 OTHER REFERENCES Bramley: J. Chem. Soc. (London), vol. 109(1916), pp. 10-45.

Merck Index, 1896, 2nd ed., p. 185.

McNair: Arch. of Dermatology and Syphilology, June 1921, vol. III, pp.802-808 (Reprint 7 pp., p. 2 of reprint pert).

1. A SUBSTANTIALLY WATER-FREE, PHENOLIC, GERMICIDAL COMPOSITION THAT ISADAPTED AS SUCH FOR DIRECT LOCAL APPLICATION, SAID COMPOSITIONCOMPRISING A HIGHLY CAUSTIC PHENOL IN SUBSTANTIALLY HOMOGENEOUS PHYSICALADMIXTURE WITH A NITROGENOUS POLAR MATERIAL WHOSE MOLECULAR STRUCTURE ISRENDERED PREPONDERANTLY ANIONOID IN CHARACTER BY THE PRESENCE THEREIN OFAN EFFECTIVE NUMBER OF ELECTRON-DONATING POLAR GROUPS, SAID POLARMATERIAL BEING FURTHER CHARACTERIZED (A) BY BEING CHEMICALLY COMPATIBLEWITH THE CAUSTIC PHENOL, AND (B) BY BEING CAPABLE OF FORMING ASUBSTANTIALLY HOMOGENEOUS PHYSICAL SYSTEM WITH MORE THAN ITS WEIGHT OFTHE CAUSTIC PHENOL, THE POLAR MATERIAL IN SAID PHYSICAL SYSTEM-WHEN SAIDSYSTEM, SO FORMED, IS APPLIED TO A SUBSTANTIALLY DRY, CUTANEOUSSURFACE-CAUSING THE PHENOL THEREIN TO EXHIBIT A DELAY IN THE TIME OFONSET OF ITS CAUSTIC EFFECT OF AT LEAST 100 PERCENT BEYOND THE TIME OFONSET OF CAUSTIC EFFECT OF A CONTROL MIXTURE CONTAINING THE SAME PHENOLIN THE SAME PROPORTION BY WEIGHT AS IN SAID PHYSICAL SYSTEM, BUT WITHSAID POLAR MATERIAL BEING SUBSTITUTED IN THE CONTROL MIXTURE BY ASUBSTANTIALLY NONPOLAR HYDROCARBON OF THE CLASS CONSISTING OFCYCLOHEXANE, PINENE, P-XYLENE AND A MIXTURE OF ISOMERIC XYLENES, SAIDPOLAR MATERIAL BEING AN ACIDULATED AMINE, SAID COMPOSITION CONTAININGTHE CAUSTIC PHENOL IN AN EFFECTIVE GERMICIDAL CONCENTRATION, AND SAIDACIDULATED AMINE BEING PRESENT IN THE COMPOSITION IN AN AMOUNTSUFFICIENT TO REDUCE THE CAUSTICITY OF THE PHENOL WITHOUTPROPORTIONATELY REDUCING ITS GERMICIDAL POWER.